Intermediate products and processes for the preparation thereof



Patented Tune 5, 1951 vUNITED STATES, PATENT OFFICE INTERMEDIATE PRODUCTS AND PROC- ESSES FOR THE PREPARATION THEREOF Melvin S. Newman, Columbus, Ohio assignor to The Ohio State University Research Foundation, Columbus, Ohio, a corporation of Ohio No Drawing. Original application May 10, 1947,

Serial No. 747,178. Divided and this application July 1, 1950, Serial No. 171,743

2 Claims.

where R. is a lower alkyl group and where Y is a hydroxyl or an ester thereof and to methods for their preparation.

The products of this invention are of value in the further synthesis of other chemical compounds and are of particular value in syntheses leading to the preparation of vitamin A and derivatives of vitamin A. Prior to this invention, the products of this invention have not been known nor have there been any recognized methods for their preparation.

By this invention I synthesize alkoxy methylhexyne diols and their esters. The alkoxy methylhexyne diols which I have synthesized all had alkoxy groups.

By the use of the word alkoxy in the last sentence, elsewhere in this specification and in the claims, I mean a compound having a alkyl group attached to the remainder of the molecule by oxygen where the alkyl group has not more than six carbon atoms and I so define the term alkoxy wherever used herein. Compounds having an alkyl group with more than four carbon pounds involved may be more difiicult to handle v A further object is the provision of methods for the preparation of monoesters of a 6-alkoxy-4- methy1hexyne-2-dio1-L4.

The process of my invention may be more readily understood by reference to the following illustrative equations, where R has the value given above, and where equations 1 to 4 illuustrate the use of a magnesium halide reagent while equations 5 to 8 illustrate the use of a lithium reagent.

water.

during the'hydr'oly'sisl 'when water alone is used,

In general the process of this invention comprises the reaction of an organo-metal derivative with propargylalcohol to prepare. a p pargyl alcoholmet'al idrivativa} a metal atom replacing the hydrogen of the hydroxyl group and another replacing the acetylenic hydrogen. The.

'metal derivative is then reacted with an alkoxy butanone, to give a metal complex additioniproduct. The metal complex addition product is then hydrolyzed to give an alkoxymethylhexyne diol.

The alkoxy methylhexyneld-iol.may bereacted with an organic acid, acid halide pracid anhydride to give an acyloxy hydro zy alkoxy methylhexyne- Among the metals suitable-for theformation of a C-M derivative of propargyl alcohol are magnesium and lithium as given in the aboveex amples; other alkali metals such as sodium and potassium; alkaline earth .metalssuch as calcium, magnesium-halide residues MgX).; and .other metals. The metal derivatives of propargyl alcohol are suitably made by reacting propargyl alcohol with another suitable organo metal derivative which will eggchange the acetylenic hydrogen. S uitable"' 'reagents for the preparation of the propargyl'metal derivatives are the Grignard Reagents (RMgX) (where R is a hydro,-

carbon radical) and metal alkyls (R'M) (where M'may' be any of the metals mentioned above) although the preferred reagents are magnesium reagents and-phenyl and butyl lithium, it being understood, however, that others are within the scope of this invention. The hydrogen of the alcohol is also exchanged for the metal in the ame manner as.- -.-the.-acetyleni c hydrogen,- but the oxygen-metal derivative so formed does not undergo the addition reactions as does the carbon-metal derivative.

vents which are inert and can be obtained an- -hydrous;

Dieth ylether or a mixture of diethyl ether and tetrahydrofurane are preferred sol- The metal attached to r thecar-bon upon reactionwith the butanone be- 40 vents in whichthe reaction may be conducted. 175-.

The hydrolysis of the addition" complex result ing from the addition of the propargyl metal derivative and-the ketone is preferably done with If desired, the reaction may be cooled metal hydroxides and basic metal salts may precipitate which may make isolation of the product diflicult. The addition of small quantities of acids such as hydrochloric;sulfuric and acetic or small quantitatives of inorganic salts such as,

ammonium salts to the water used for hydrolysis is advantageous as it renders these precipitates wa'ter' soluble oroth'erwi'se easily removed. The

preferred embodiment of this invention provides for the use of such an agent during hydrolysis,

but of such kind and in such amount that it will not reactwithany of 'th constituents j'of the "reaction mixture in any way so as to-lead to products other than those which are an object of this invention. f

The e'sterifi'cation of thehydroxyl group on carbon atom number one-is accomplished by an While the forms of embodiments of the present invention as herein disclosed constitute preferred lowing structural formula:

4 acid or acid derivative such as an acid halide or the acid anhydride which are equivalents for the esteriiication of the diol. Any organic ester may be used. However, for ease of manipulation in subsequent reactions, esters of lower molecular weight fatty acids are preferred.

The nature of the alkoxy group on the alkoxy butanone which is condensed with the metal derivative of propargyl alcohol determines the na- 10 ture of the alkoxy group in the product of this invention. This R may be any hydrocarbon radical'suchas alkyl,-.cycloalkyl, aralkyl, and aryl. In the preferred embodiment of this invention,

R is a lower alkyl group such as one having four carbon atoms or less. Other hydrocarbon radi- "cals are operative but in subsequent reactions the compounds involved may be more diflicult to handle due to higher boiling temperatures.

EXAMPLE I Preparation of 6-metho:cy-4-methylhe:cyne-2- dioZ-I ,4

A solution of 112 g. (2 moles) oflpropargyl'alcohol in 400 cc. of dry ether was added dropwise over three hours to 2710 cc. of a stirred solution of 1.57N (4.25 moles) butylm'agnesium chloride in ether. The solution was stirred at room temperature for an additional hour and then a solu- ..tion of 224 g. (2.2 moles) of 4-methoxybutanone- 2 added over a period of two hours. After stirring overnight, the solution was hydrolyzed with 700 cc. of saturated ammoniumchloride solution. The ether layer was separated, concentratedand the residue distilled under reduced pressure.

The product was obtained as a yellowish oil,

B. P. 122--125 C. at 1-110 2 mm; yl61d=132.5

Analysis:.

Calcd. for CsHmOa: C, 60.7; H, 8.9. Found: 'C, 61.3, 61.2; H, 9.3, 9.1. The product has the following structural formula:

on, CHr-CEC(JCH2-CH;OCH

on H

In addition, 3'7 g. (33% of propargyl alcohol) (B. P. 109111 C.) was recovered from the low boiling fractions.

EXANIPLE II Preparation of 1-acetoady-fi-methoary-et mlethylheryne-Z-oZ-el To acooled (510 C.) solution of 198 g. (1.26 moles) of 6-1nethoxy-4-methylhexyne-2-diol-1,4 in 300 cc. (3+ moles) of dry pyridine was added .in portions over forty-five minutes 163 g. (1.6

moles) of acetic anhydride. The solution Was allowed to warm up to room temperature and ,stand overnight.

The desired product was isolated by distillation at reduced pressure; B. P. -112 C. at 1 mm; yield=237 g. (94%) n =1.4590. It has the folforms, it is to be understood that other forms might be adopted, all coming within the scope of the. claims which fo11ow..:... j

5 6 i claim: 2. As a composition of matter, a compound 1. As a composition of matter, a compound represented by the formula represented by the formula 03 5 HOCH OEC( JCH OH OCH HOCHgCEO-L|:|CHg-CHg-OR H3 MELVIN s. NEWMAN.

wherein R is a lower alkyl group.

No references cited. 

1. AS A COMPOSITION OF MATTER, A COMPOUND REPRESENTED BY THE FORMULA 